J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.436 on 1 October 1998. Downloaded from 436 J Neurol Neurosurg Psychiatry 1998;65:436–445 NEUROLOGY AND MEDICINE Dystonia and chorea in acquired systemic disorders Jina L Janavs, Michael J AminoV Dystonia and chorea are uncommon abnormal Associated neurotransmitter abnormalities in- movements which can be seen in a wide array clude deficient striatal GABA-ergic function of disorders. One quarter of dystonias and and striatal cholinergic interneuron activity, essentially all choreas are symptomatic or and dopaminergic hyperactivity in the nigros- secondary, the underlying cause being an iden- triatal pathway. Dystonia has been correlated tifiable neurodegenerative disorder, hereditary with lesions of the contralateral putamen, metabolic defect, or acquired systemic medical external globus pallidus, posterior and poste- disorder. Dystonia and chorea associated with rior lateral thalamus, red nucleus, or subtha- neurodegenerative or heritable metabolic dis- lamic nucleus, or a combination of these struc- orders have been reviewed frequently.1 Here we tures. The result is decreased activity in the review the underlying pathogenesis of chorea pathways from the medial pallidus to the and dystonia in acquired general medical ventral anterior and ventrolateral thalamus, disorders (table 1), and discuss diagnostic and and from the substantia nigra reticulata to the therapeutic approaches. The most common brainstem, culminating in cortical disinhibi- aetiologies are hypoxia-ischaemia and tion. Altered sensory input from the periphery 2–4 may also produce cortical motor overactivity medications. Infections and autoimmune 8 and metabolic disorders are less frequent and dystonia in some cases. To date, the causes. Not uncommonly, a given systemic dis- changes found in striatal neurotransmitter order may induce more than one type of dyski- concentrations in dystonia include an increase nesia by more than one mechanism. in noradrenaline and a decrease in dopamine concentrations. The areas of the brain associated with particular movement disorders have been determined by cerebral imaging and necropsies Hypoxic-ischaemic causes School of Medicine, of patients, and by animal lesioning studies.5–7 MECHANISMS University of Based on such data, chorea seems to result Chorea and dystonia may result from hypoxia- California, San ischaemia due to global cerebral hypoperfusion Francisco, CA, USA from hypofunction of the indirect pathway from the putamen to the internal globus or cellular hypoxia, such as in toxic mitochon- http://jnnp.bmj.com/ J L Janavs drial dysfunction. Two hypotheses have been M J AminoV pallidus, and dystonia correlates more strongly with hyperfunction of the direct relative to the put forward to explain hypoxic-ischaemic injury to the basal ganglia: selective hypoper- Correspondence to: indirect pathway between the putamen and Dr MJ AminoV, Box 0114, fusion of certain vascular territories and an internal globus pallidus, both resulting in inap- Room M-794, University of intrinsic metabolic susceptibility of the stria- California, San Francisco, propriate disinhibition of thalamic projections tum to hypoxia-ischaemia due to its high CA 94143, USA. Telephone to the premotor and motor cortex (figure). 001 415 476 1986. oxidative metabolism.7 The internal segment Chorea has been most consistently associated and the medial outer segment of the globus on September 24, 2021 by guest. Protected copyright. Received 16 February 1998 with lesions in the caudate nucleus or puta- pallidus are supplied by the anterior choroidal and in revised form men, resulting in disinhibition of the external 26 May 1998 artery, and the caudate head and putamen are globus pallidus. Lesions of the subthalamo- fed by the lenticulostriate artery. Changes in Accepted 1 June 1998 internal pallidal pathway also result in chorea. perfusion may randomly aVect either or both Table 1 Aetiologies of secondary chorea and dystonia* vessels, or one vessel preferentially if other vas- cular lesions are also present. Primary cause Mechanism There is often a delay in onset of the Hypoxia-ischaemia Global hypoperfusion movement disorder after hypoxic injury, which Toxins Cellular (mitochondrial) injury may reflect the time required for remyelination, Neurotransmitter imbalance Receptor antagonism inflammatory changes, ephaptic transmission, Receptor stimulation Neurotransmitter reuptake inhibition oxidation reactions, maturational or aberrant Neurotransmitter depletion synaptic reorganisation, trans-synaptic neuronal Altered neurotransmitter turnover degeneration, or denervation supersensitivity to Infection Vasculopathy due to antibodies or organism 4 Antibodies to basal ganglia epitopes occur. Direct basal ganglia invasion by the organism As discussed earlier, dystonia and chorea Neuronal injury by an elaborated cytotoxin Antibody mediated Vasculopathy most commonly result from striatal dysfunc- Cross reaction with basal ganglia epitopes tion, and hypoxia-ischaemia has been shown Metabolic disorders Endocrine dysfunction to alter several neurotransmitter systems in the Electrolyte abnormalities striatum. Glutamate is the main neurotrans- *More than one mechanism may be involved in the generation of specific dyskinesias. mitter in cortical neurons projecting to the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.436 on 1 October 1998. Downloaded from Dystonia and chorea in acquired systemic disorders 437 striatum and may contribute excitotoxic in- produces cocontraction of opposing muscle jury. Hypoxia-ischaemia has been shown to groups on reaching, as in dystonia.9 Extra- increase striatal extracellular glutamate, and cellular dopamine concentrations rise and decrease glutamate transporter concentra- concentrations of dopamine metabolites fall tions. Direct lesioning of the globus pallidus after hypoxia-ischaemia.710 Dopamine may with excitatory amino acids in monkeys also potentiate the excitotoxic properties of glutamate, and depleting the striatum of dopamine before hypoxia-ischaemia decreases the degree of striatal injury. In the neonatal rat model of cerebral hypoxia-ischaemia, striatal D1 and D2 dopamine receptor numbers fluctuate until 9 to 11 weeks after injury, at which time the D1 receptor number has returned to normal but the reduction in D2 receptors persists.11 Hypoxia-ischaemia also results in areas of complete loss of pre- proenkephalin mRNA in the dorsal striatum of the rat brain.12 Enkephalin, together with GABA, is an inhibitory neurotransmitter in the projections from the putamen to the external pallidum. Hypoxic-ischaemic necro- sis of medium sized spiny striatal neurons may be responsible for decreased concentra- tions of the inhibitory neurotransmitter, GABA. By contrast, the striatal cholinergic system remains relatively preserved or even upregulated after hypoxia-ischaemia, as evi- denced by an increase in cholinergic fibres and cell bodies, and an increase in acetylcholine release.13 This is interesting in that anticholin- ergic medications often ameliorate dystonic movements. CLINICAL FEATURES Global cerebral hypoxia-ischaemia is most often a cause of dystonia and chorea when it occurs perinatally. However, regardless of aeti- ology or timing, it may also cause movement disorders in children and adults. Despite the global insult, patients often have focal or unilateral findings clinically and on imaging studies. Uncommonly, brain CT or MRI is http://jnnp.bmj.com/ normal or discloses mild diVuse atrophy. PERINATAL HYPOXIC ISCHAEMIA Perinatal hypoxic-ischaemic injury may result in any pattern of dystonia, often after an impressive interval of time. Summarising data from three studies of 37 patients, the latency of onset ranged from 6 to 58 years, and usually on September 24, 2021 by guest. Protected copyright. began as a focal, and rarely, segmental dystonia. In most patients, the dystonia became more extensive over a range of 6 months to 28 years such that it progressed to segmental dys- tonia in 41%, developed into hemidystonia in 27%, and became generalised in 24%.41415 However, the longer the interval between the Thalamocorticobasal ganglionic circuitry. (A) Normal. The striatum receives inputs from the cortex and SN and projects to the Gpi through direct and indirect pathways. The direct pathway mediates GABA-ergic inhibition of the GPi. The indirect pathway projects to the GPi by way of the GPe and STN. The GPi maintains inhibitory tone on thalamocortical projections. (B) In chorea, there is underactivity of the indirect pathway due to dysfunction (X) either of the striatum or STN, with resultant disinhibition of the thalamus. (C) In dystonia, overactivity of the direct pathway is postulated, resulting in disinhibition of thalamic projections to the cortex. GPe/i=globus pallidus externa/interna; SN=substantia nigra; STN=subthalamic nucleus; GABA=ã-aminobutyric acid; Glu=glutamate; DA=dopamine; —>=excitatory; - - ->=inhibitory. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.436 on 1 October 1998. Downloaded from 438 Janavs, AminoV hypoxic insult and the development of dysto- cerebral catecholamines and serotonin in older nia, the less certain is an aetiological relation, people, resulting in receptor upregulation; the emphasising the importance of a complete oestrogen deficit in postmenopausal women, evaluation for other causes. These studies did resulting in dopamine receptor hypersensitivity; not correlate the aetiology or duration of the